The severity of an asthmatic attack is the product of the disease process and the effectiveness of the opposing physiological defense mechanisms and available drug therapy. There is increasing evidence that the defense mechanism may be (or become) defective because of an imbalance between Alpha and Beta receptor function. There are also some data which suggest a diminished intensity of adrenergic drive to these receptors. This research proposal describes a plan for testing the hypotheses that prolonged treatment with Beta agonists may decrease the number and function of Beta receptors and that this may be associated with a parallel increase in Alpha receptors. We also seek to examine the effect of graded doses of steroids on Alpha and Beta receptors of normal subjects and in mild and moderately severe asthmatics all of whom will be exposed to Beta agonists. The latter group will also receive theophylline. In vivo studies, measuring bronchomotor responses and pupillary changes will be complemented and extended by in vitro examination of Alpha and Beta receptors in lymphocytes from these subjects. In these studies we will examine the effects of chronic exposure to theophylline and isoproterenol on Alpha and Beta receptors. We will extend our present observations on the effect of steroids on these changes, and will also examine the effects of increasing GTP levels on the desensitization process. We wish also to examine the intensity of adrenergic response (plasma or urinary catecholamines) to the disease, and to experimentally-induced bronchospasm in normals and mild asthmatics, in order to confirm or refute the suggestion that asthmatics may in this respect exhibit some fundamental deficiency.